The ATBC Cohort Follow-up Study has been in place since 1994. Male smokers between the ages of 50 and 69 were recruited from southwestern Finland between April 1985 and June 1988. A total of 29,133 men were randomly assigned to one of four intervention groups: 50 mg/day alpha-tocopherol (as dl-alpha-tocopheryl acetate); 20 mg/day beta-carotene; both alpha-tocopherol and beta-carotene; or placebo. They were followed for five to eight years during the trial, until death, or 30 April 1993 when intervention was stopped (median follow-up, 6.1 years). Follow-up for endpoints was continued postintervention. Following invitation for participation and recruitment through a population-based postal survey, the trial randomly assigned 29,133 Caucasian 50-69 year old male smokers of 5 cigarettes daily to one of four intervention groups based on a 2x2 factorial design: beta-carotene (20 mg/day), vitamin E (50 mg/day, as dl-alpha-tocopheryl acetate), both agents, or placebo. At entry, medical, dietary, smoking, and occupational data were obtained, along with physical measurements, a chest x-ray, and serum and toenail samples. Diet was captured through a 276 food item dietary questionnaire that was developed and validated for the trial. Baseline serum was collected, frozen, and stored for all participants, and vitamin E, beta-carotene, retinol, and total and HDL cholesterol were determined. Follow-up serum and whole blood were collected for all active participants later in the study, as were additional serum and red blood cell samples from selected subsets. Active intervention continued for 5-8 years, with three study visits annually during which participants were asked about their health and possible subjective side effects, capsule compliance, and smoking habits since the last visit. Chest films were taken at 2-3 year intervals and at the end of the trial. All incident cancers were identified through the nationwide Finnish Cancer Registry, medical records/pathology slides were reviewed / abstracted, and deaths/underlying causes were identified through the National Population Register. The ATBC Cohort Follow-up Study has had the overall aim of conducting cancer etiologic research and post-intervention cancer surveillance based on the original trial cohort of 29,133 men. Cohort analyses, nested case-control investigations, analyses of genetic polymorphisms and other molecular parameters, and studies of the biological effects of the intervention agents on relevant biomarkers have been conducted and are the focus of ongoing research. Current cumulative totals of diagnosed cases through 2012 include approximately 3,900 lung, 2,700 prostate, 900 colorectal, 800 bladder, 400-500 each for stomach, pancreas, and kidney cancers, and 450 head and neck. Cancer etiologic research in the ATBC Study has evolved naturally from the focus on supplementation into several areas of concentration that reflect both our research interests and the availability of study resources to a continually growing number of highly productive investigators both at NCI and elsewhere. A public website (http://atbcstudy.cancer.gov/) provides information regarding the project's research, data, personnel, and resources, including procedures for initiating collaborations. The high-quality study data, biological specimens, and ongoing endpoint ascertainment have been applied to testing biochemical and genetic hypotheses related to nutritional and other factors having potentially high attributable risks in prostate (based on 2,500 cases), lung (3,500 cases), colorectal (700 cases), pancreatic (400 cases) and other cancers. GWAS studies of risk for prostate, lung, renal, and bladder cancers, as well as NHL and glioma are completed. We have completed investigations of vitamins D, E, A and selenium status; carotenoids and other antioxidants; one-carbon metabolism; energy balance, insulin, and growth factors; sex steroids; and genetic variants impacting these exposures. GWAS studies of nutrition phenotypes such as serum vitamin D status are being conducted. Evaluation of these factors within the context of the controlled vitamin supplementation design has afforded us unique opportunities to investigate biological and biochemical interactions.Another important dimension of the ATBC Study has been collaborations with extramural researchers in cancer epidemiological consortia. These include: the NCI Breast and Prostate Cancer Cohort Consortium (BPC3), PanScan, the Pooling Project of Prospective Studies of Diet and Cancer, and the Harvard Specialized Center on Folate, One-Carbon Nutrients, Gene Variants and Colorectal Cancer. We contribute scientific expertise, data and cohort resources, and intramural support to these powerful, high-impact studies.